PROJECT SUMMARY/ABSTRACT Persistent infection in diabetic wounds can increase the probability of severe complications, such as non- traumatic limb amputation. In the USA, there are more than 29 million diabetics, with approximately 1.7 million new cases every year. About 3-4 million new diabetic ulcers are diagnosed every year, and these numbers are increasing as our population ages. Around 25% of all diabetic patients will develop a foot ulcer, and a fifth of these cases will result in a chronic non-healing wound that requires amputation. The response to infection is often delayed in diabetic wounds, which leads to further impaired healing. Thus, a significant need exists towards the development of multifunctional strategies that not only locally support and enhance the wound healing process but could also reduce wound bacterial colonization. Supplemental local wound oxygen delivery is a practical approach to reduce the bacterial population of wound and enhances impaired immune mechanisms that are dependent on sufficient oxygen tensions to generate antimicrobial reactive oxygen species (ROS) and work effectively. There is growing evidence supporting the antibiotic action of oxygen for upregulating endogenous ROS and leukocyte activation. Topical oxygen does not exhibit unfavorable systemic side effects from hyperoxia that are often associated with systemic clinical oxygen delivery approaches, such as hyperbaric oxygen therapy (HBOT). Diabetic wounds are often stricken with infection as well, and heavy wound bacterial burden typically requires systemic or topical treatments with appropriate antibacterial chemicals. Topical antibacterial treatment can help localize the drug and limit systemic toxicity. Oxygen can also be essential for the effective function of antibacterial agents. Accordingly, we have developed a unique strategy for topical oxygen delivery via perfluorocarbon-modified chitosan hydrogels (MACF) that can provide significant supplemental oxygen locally to a wound to enhance the wound healing process in animal models. Combining this unique material with a controlled release system for an effective chemical antibacterial agent will allow us to produce a synergistic wound dressing with potentially enhanced ability to reduce infection and to maintain this favorable statues for a proloned period of time. This proposal is hypotheses that reducing diabetic wound infection is accelerated by localized oxygen bioavailability, via upregulated leukocyte activation and antibacterial ROS generation, and that the impact of an antibacterial agent can be improved synergistically through oxygen availability to further inhibit the growth of Gram-positive and Gram-negative bacteria. This overall hypothesis will be tested in two Specific Aims: Aim 1: To determine oxygenating MACF?s ability to reduce infection in diabetic wounds while revealing a new basic understanding of the role of supplemental oxygen in this process. Aim 2: To create a multifunctional anti-bacterial oxygenating MACF wound dressing able to reduce infection in diabetic wounds. The effects of our treatments will be evaluated by studying the tissue and molecular level responses during wound healing and infection control.